A-acylthio-p-cyclohexylphenylacetic acid and derivatives

ABSTRACT

Novel Alpha -mercapto-p-cycloalkylphenylacetic acids and their derivatives have been prepared. Compounds of this invention possess useful anti-inflammatory, analgesic and antipyretic properties.

United States Patent 1191 1111 3,821,267

Diamond et al. 1 June 28, 1974 A-ACYLTHlO-P-CYCLOHEXYLPHENYLA- [56} References Cited CETIC ACID AND DERIVATIVES UNITED STATES PATENTS [75] Inventors: Julius Diamond, Lafayette Hill; 3,098,078 7/1963 Drvey et al. 260/516 Norman Julian Santora, Roslyn, 3,385,886 5/1968 Nicholson et al 260/576 both f 3,435,075 3/1969 Glamkonski et a] 260/590 7 3,457,300 7/1969 Dom et al 260/516 Asslgneel William Rorer, 3.513,190 5/1970 Crag0e,Jr1 et al. 260/455 R Washmgton' FOREIGN PATENTS OR APPLICATIGNS [22] Wed: June 1971 7.100.020 1/1971 Japan 260/516 1 1 pp N94 152,451 OTHER PUBLICATIONS Related US. Application Data lskander et al., Carbon-Sulphur Fission in Thio- [63] Continuation-impart of Ser. No. 34,870, May 5, 2 l 1961, PP- 239397 Reeve et al., The Syn. of aMethoxy Phenylacetic [52] US. Cl. 260/455 R, 260/247, 260/247.1, Acids Etc., (1959) J.A.C.S. 82 pp. 4062-66 (1960).

260/247.2 A, 260/247.2 B, 260/268 R, 260/268 C, 260/268 AK, 260/268 CN, Primary ExaminerGlennon H. Hollrah 260/293.65, 260/293.l2, 2600.93.73, 260/293.74, 260/293.75, 260/293.77, 57 ABSTRACT Novel a-mercapto-p-cycloalkylphenylacetic acids and 260/293'83 260/29384 260/3067 260/443 their derivatives have been prepared. Compounds of 51] Int Cl C07c 153/07 this invention possess useful anti-inflammatory, anal- [58] Field of Search 260/455 R, 516; 424/317 gas: and pmpemes' 7 Claims, No Drawings A-ACYLTHIO-P-CYCLOHEXYLI'HENYLACETIC ACID AND DERIVATIVES CROSS REFERENCES TO RELATED APPLICATIONS This is a continuation-in-part application of Ser. No. 34,870 filed May 5, 1970.

SUMMARY OF THE INVENTION pounds of this invention are administered to mammals, they afford significant treatment of inflammation and associated pain and fever.

They further provide analgesic and antipyretic methods for the relief and treatment of pain and fever associated with inflammation.

BACKGROUND OF THE INVENTION There have been continued efforts in research to develop drugs which would significantly inhibit the development of inflammation and relieve the pain and fever associated with it. Much of these effects have been carried on in the field of steroids. While many of these compounds have been effective, they have had the drawback of causing many side effects.

We have unexpectedly found that a-mercapto-pcycloalkylphenylacetic acid compounds and their derivatives have valuable pharmacologic properties.

We have found that a-mercapto-p-cycloalkylphenylacetic acid compounds and their derivatives possess useful anti-inflammatory, analgesic and antipyretic properties.

We have also found a series of anti-inflammatory compoundswhich are non-steroidal.

We have further found that these a-mercapto-pcycloalkylphenylacetic acid compounds and their derivatives are novel.

We have also found that the compounds of this invention are useful in effectively providing a method for the inhibition of inflammation and the treatment of associated pain and fever.

We have still further found an entirely new class of anti-inflammatory, analgesic and antipyretic pharmaceutical compositions containing the a-mercapto-pcycloalkylphenylacetic acids and derivatives of this invention as active ingredient.

We have again found a convenient method for synthesizing these compounds.

DESCRIPTION AND PREFERRED EMBODIMENT This invention comprises a class of novel chemical compounds which contain a cycloalkyl radical which is attached to a substituted phenyl-a-mercaptoacetic acid in the para-position. This invention further comprises derivatives of said acetic acids and the method of preparing the same.

This invention also describes a new method of treating inflammation and associated pain and fever as well as novel therapeutic compositions.

The compounds of this invention can be represented by the generic structure which is described by the genrslierwla where:

n is 0-2;

B is hydrogen or loweralkyl;

R is halo, nitro, amino, acylamino, mono- & diloweralkylamino, mercapto, acylthio, loweralkylthio, loweralkylsulfinyl, loweralkylsulfonyl, hydroxy, loweralkoxy, acyloxy, haloloweralkyl,

cyano, acetyl or loweralkyl;

R is hydrogen,

fluoro, chloro, bromo, trifluoromethyl, cyano, nitro or Ioweralkylsulfonyl;

X is mercapto,

acylthio, carboxyacylthio, aroylthio, carboxyaroylthio, loweralkoxythiocarbonylthio, loweralkoxycarbonylthio, arloweralkoxycarbonylthio, amidinothio, thiocyanato, thiosulfo, thioacylthio, diloweralkylthiocarbamylthio, carbamylthio, loweralkylcarbamylthio, diloweralkylcarbamylthio, loweralkylthio, loweralkylsulfinyl, loweralkylsulfonyl, sulfino or sulfo; and

Z is OH,

loweralkoxy, arloweralkoxy, 2. loweralkylamino, diloweralkylamino, cycloloweralkylamino,

A N A (where A is loweralkylidenyl or heteroloweralkylidenyl),

NHOH,

OM (where M is an alkali, alkaline earth or aluminum metal or an ammonium salt).

The compounds of this invention contain an asymmetric carbon atom in the alpha-position of the acetic acid side chain. As a result, the above compounds of formula I may be obtained as racemic mixtures of their dextro and levorotatory isomers. It is to be unt derstood that said d and l isomers as well as the dl mixtures thereof are embraced within the scope of this invention.

When B is loweralkyl, two racemic mixtures may exist in the case of 2- or 3'- loweralkylcyclohexylphenyl-a-mercaptoacetate, 2'- or 3'-loweralkylcyclopentylphenyl-a-mercaptoacetate, 2'- or 3'- or 4'-loweralkylcycloheptylphenyl-amercaptoacetate or their derivatives. It is understood that both racemic mixtures are embraced within the scope of this invention.

The preferred R and R substituents are in the 3 and 5 positions.

The preferred compounds of this embodiment describe the cyclohexyl class of chemical compounds which have particularusefulness as anti-inflammatory, analgesic and antipyretic agents. These compounds are described in formula ll where:

R, R, X and Z are as described above.

Those compounds whose properties are even more loweralkylsulfinyl, loweralkylsulfonyl, sulfino or sulfo; and Z is OH,

loweralkoxy, arloweralkoxy, Z, loweralkylamino or OM. The most preferred compounds of this invention describe a class of chemical compounds which have particular usefulness as anti-inflammatory, analgesic and antipyretic agents. These compounds are described in formula ll where:

R is halo, nitro, loweralkylsulfonyl, haloloweralkyl or cyano;

R' is hydrogen,

chloro, bromo or nitro;

X is mercapto,

acylthio, aroylthio, loweralkoxythiocarbonylthio, loweralkoxycarbonylthio, thiosulfo, carbamylthio, loweralkylcarbamylthio, diloweralkylcarbamylthio; and

Z is OH,

loweralkoxy, arloweralkoxy, z, loweralkylamino or OM.

A special embodiment of this invention which describes novel compounds that are effective in inhibiting inflammation and the treatment of pain and fever associated with inflammation as well as having analgesic and antipyretic effectiveness for the relief and treatment of pain and fever not symptomatically related to an inflammation indication are described by formula III 3X was.

R III where:

R is chloro, bromo, nitro, methylsulfonyl, trifluoromethyl or cy n R eli ism.-

bromo or nitro',

X is hydrogen,

acyl, aroyl, loweralkoxythiocarbonyl, loweralkoxycarbonyl, sulfo, carbamyl, loweralkylcarbamyl, diloweralkylcarbamyl; and the salts thereof.

Included within the scope of this further special embodiment are the racemic mixtures as well as the dextro and levorotatory isomers thereof.

In the descriptive portions of this invention, the following definitions apply:

The term loweralkyl refers to a loweralkyl hydrocarbon group containing from one to about six carbon atoms which may be straight chained or branched.

The acyl radical may be any organic radical derived from an organic acid by the removal of its hydroxyl group such as formyl, acetyl, propionyl, 3-carboxypropionyl, 3-carboxy-2-propenoyl, campho ryl, benzoyl, toluoyl or heteroyl such as pyridinoyl, piperidinoyl, thenoyl, etc.

Loweralkoxy signifies an alkoxy group containing from one to about six carbon atoms which may be straight chained or branched.

The preferred aroyl is benzoyl, loweralkylbenzoyl such as toluoyl or halobenzoyl such as p-chlorobenzoyl, 2-carboxybenzoyl, etc.

The term loweralkylidenyl refers to a loweralkylidenyl hydrocarbon group containing from two to about six carbon atoms.

Heteroloweralkylidenyl refers to a loweralkylidenyl hydrocarbon group-containing from about two to five carbon atoms and having one or more hetero atoms in the chain selected from O, N or S, such as piperidinyl, morpholinyl, etc.

The preferred alkali or alkaline earth metals are sodium, potassium, calcium and magnesium.

The term ammonium salt refers to the cation formed when ammonia or an organic amine react with the carboxyl group to form ammonium salts of the structure given in the formula. The ammonium salts are formed with a (1) loweralkylamines such as methylamine, diethylamine, triethylamine; (2) hydroxyloweralkylamines such as B-hydroxyethylamine, (3) heterocyclic amines such as 2-aminopyridine, piperazine, piperidine; (4) aralkylamines such as a-methylbenzylamine, phenethylamine; (5) cycloalkylamines such as cyclohexylamine; (6) alkaloids such as quinine, cinchonidine, cinchonine, ephedrine.

Representative compounds of this invention which are particularly useful are as follows:

a-mercapto-3-chloro-4-cyclohexylphenylacetic acid a-acetylthio-3-chloro-4-cyclohexylphenylacetic acid a-propionylthio-3 -chloro-4-cyclohexylphenylacetic a-l JiTS ryIthiO-S-chloro-4-cyclohexylphenylacetic a-b hff enoylthio-ii-chloro-4-cyclohexylphenylacetic a-Ziiijzoylthio-B-chloro-4-cyclohexylphenylacetic 6 a-(a-toluoylthio )-3chloro-4-cyclohexylphenylacetic acid a-(o-carboxybenzoylthio)-3-chloro-4-cyclohexylphenylacetic acid a-methoxythiocarbonylthio-3-chloro-4-cyclohexylphenylacetic acid oz-ethoxythiocarbonylthio-3-chloro-4-cyclohexylphenylacetic acid a-methoxycarbonylthio-3-chloro-4-cyclohexylphenylacetic acid a-ethoxycarbonylthio-3-chloro-4-cyclohexylphenylacetic acid a-benzyloxycarbonylthio-3-chIoro-4-cyclohexylphenylacetic acid a-thioformylthio-3-chloro-4-cyclohexylphenylacetic acid a-amidinothio-3-chloro-4-cyclohexylphenylacetic acid a-thiocyanato-3-chloro-4-cyclohexylphenylacetic acid a-thiosulfo-3-chloro-4-cyclohexylphenylacetic acid a-carbamylthio-3-chloro-4-cyclohexylphenylacetic acid a-ethylcarbamylthio-3-chloro-4-cyclohexylphenylacetic acid a-dimethylcarbamylthio-3-chloro-4-cyclohexylphenylacetic acid a-diethylcarbamylthio-3-chloro-4-cyclohexylphenylacetic acid a-methylthio-3-chloro-4-cyclohexylphenylacetic acid a-ethylthio-3-chloro-4-cyclohexylphenylacetic acid a-propylthio-3-chloro-4-cyclohexylphenylacetic acid a-i-propylthio-3-chloro-4-cyclohexylphenylacetic acid a-methylsulfinyl-3-chloro-4-cyclohexylphenylacetic acid a-methylsulfonyl-3-chloro-4-cyclohexylphenylacetic acid a-sulfino-3-chloro-4-cyclohexylphenylacetic acid a-sulfo-3-chloro-4-cyclohexylphenylacetic acid a-acetylthio3-fluoro-4-cyclohexylphenylacetic acid a-acetylthio-3-bromo-4-cyclohexylphenylacetic acid a-acetylthio-3-iodo-4-cyclohexylphenylacetic acid a-acetylthio-3-nitro-4-cyclohexylphenylacetic acid a-acetylthio-3-trifluoromethyl-4-cyclohexylphenylacetic acid a-acetylthio-3-mercapto-4-cyclohexylphenylacetic acid a-acetylthio-3-acetylthio-4-cyclohexylphenylacetic acid a-acetylthio-3-methylmercapto-4-cyclohexylphenylacetic acid a-acetylthio-3-methylsulfinyl-4-cyclohexylphenylacetic acid aacetylthio-3-methylsulfonyl-4-cyclohexylphenylacetic acid a-acetylthio-3-cyano-4-cyclohexylphenylacetic acid a-acetylthio-3-carboxy-4-cyclohexylphenylacetic acid a-acetylthio-3-carbethoxy-4-cyclohexylphenylacetic acid a-acetylthio-3-amino-4-cyclohexylphenylacetic acid d a-acetylthio-3,5-dichloro-4-cyclopentylphenylad a-diethylcarbamylthio-3-chloro-4-cycloheptylcetic acid phenylacetic acid 1 a-acetylthio-3,5-dichlore-4-cyclopentylphenylal a-diethylcarbamylthio-3-chloro-4-cycloheptylcetic acid phenylacetic acid I d a-mercapto-3-chloro-4-cyclopentylphenylacetic 5 d a-ethoxythiocarbonylthio-3,5-dichloro-4- acid 7 cycloheptylphenylacetic acid 1 a-rnercapto-3-chloro-4-cyclopentylphenylacetic l a-ethoxythiocarbonylthio-3,5-dichloro-4cyclohepacid tylphenylacetic acid d a-benzoylthio-3,5-dichloro-4-cyclopentylphenylad a-acetylthio-3-chloro-4-cycloheptylphenylacetic cetic acid 10 acid, sodium salt l a-benzoylthio-3,5-dichloro-4-cyclopentylphenylal a-acetylthio-3-chloro-4-cycloheptylphenylacetic cetic acid a d qdiumsalt W t d a-diethylcarbamylthio-3-chloro-4-cyclopentyl- The compounds of this invention maybe prepared by phenylacetic acid the following general procedures. Condensation of a l a-diethylcarbamylthio-3-chloro-4-cyclopentyll5 cycloalkylbenzene with a loweralkyl or aralkyl oxalyl phenylacetic acid chloride in the presence of anhydrous aluminum chlord I a-ethoxythiocarbonylthio-3,5-dichlor0-4- ide results in a p-cycloalkylphenylglyoxylate. The recyclopentylphenylacetic acid suiting loweralkyl or aralkyl esters of the p-cycloalkyll a-ethoxythiocarbonylthio-3,5-dichloro-4-cyclopenphenylglyoxylic acid may then be a) halogenated; b) tylphenylacetic acid nitrated or c)alkylated to obtain the corresponding d a-acetylthio-3-chloro-4-cyclopentylphenylacetic loweralkyl esters of a 3-halo-4-cycloalkylphenylglyoxyacid, sodium salt lic acid, a 3-nitro-4-cycloalkylphenylglyoxylic acid or a l a-acetylthio-3-chloro-4-cyclopentylphenylacetic 3-alkyl-4-cycloalkylphenylglyoxylic acid. Chlorination acid, sodium salt or bromination may be carried out in the'presence of d a-acetylthio-3-chlore-4-cycloheptylphenylacetic a small amount of iodine dissolved in an inert solvent acid such as carbon tetrachloride. A solution of chlorine or l a-acetylthio-B-chloro-4-cycloheptylphenylacetic bromine is then added while the temperature is held acid near 0C. Nitration is carried out with fuming nitric d a-acetylthio-3,5-dichloro-4-cycloheptylphenylaacid at about 0C. Alkylation is carried out under Friecetic acid del Crafts conditions with an alkyl halide and alumil a-acetylthio-3,5-dichloro-4-cycloheptylphenylanum chloride. The following reaction equations illuscetic acid trate these methods.

AlCla Alk-Cl A 4101 lz or Br,

N02 I ial Allr d 7 dm ercap to-3-chloro-4-cycloheptylphenylacetic where R" is loweralkyl or arloweralkyl and Hal is id 1 chloro or bromo.

l a-mercapto-3-chloro-4-cycloheptylphenylacetic I W W n W 7V 7 V M W V h 7W 7 acid When a loweralkyl group is desired in the cycloalkyl d a-benzoylthio-3,5-dichl0r0-4-cycloheptylphe y aring, then the condensation will take place with the apcetic acid propriate loweralkyl benzene cycloalkyl followed by l a-benzoylthio-B,5-dichloro-4-cycloheptylphenylanitration, chlorination, bromination or alkylation as decetic acid i sired.

NO: Hal

o m dooon" 15 16 Appropriately desired end products having various R c. reacted with cuprous methanesulfinate in quinoand R substituents can be prepared by using suitable line at about 150C to obtain a 3-methylsulfonyl-4- reactions in order to convert one group to another. cycloalkylphenylglyoxylate: Thus, for example, a 3-halo-4-cycloalkylphenylglyoxylate in which halo is chloro, bromo or iodo may be 5 B a. reacted with cuprous cyanide in quinoline at about 6 E Gus one: l50C to produce a 3-cyano-4-cycloalkylphenylglyoxylate: H81

0 0 CuON l SQLQHLD...

Hal ,v. t w.a -.w t m l B 0 A 3-nit.ro-4-cycloalkylphenylglyoxylate may be selec-l g H tiyely hydrogenated to the corresponding amine. (C COOR A 3-amino-4-cycloalkylphenylglyoxylate "may then be N l V a; monoor dialkylated with loweralkyl halides or b. reacted with trifluoromethyliodide and copper sulfates or acylated with loweracyl chlorides or anp wd at qut 59 i d mefll lfqr amiq fltq it hydr de. t l

B I Y r B I o H 0 (m-154300?" In 0 ll :-coon" N02 v 1 NH2 0 0 a W l COOR" i)n COOR" NH; NI IR" l were; 1

0 0 (Q 01. l-coon" Hi) -JJC00R VNVBCORI -V' MIN M V Mi 1])2 obtain a 3-trifluoromethyl-4-cycloalkylphenylb. diazotized to the diazonium fluoroborate which is glyoxylate: [as described in Tetrahedron Letters: then thermally decomposed to the 3-fluoro-4- 47, 4095 (1959)] v cycloalkylphenylglyoxylate,

0 o C t) -CO0R H1) CO0R I HBF4 NH, 1 1,131?

B 0 c. diazotized and heated in an aqueous medium to LL U CFaI form the 3-hydroxy-4-cycloalkylphenylglyoxylate (C5) COOK or heated in an alcohol to form the 3-alkoxy-4- cycloalkylphenylglyoxylate. The hydroxyl group may also be alkylated with loweralkyl halides or B O sulfates to the alkoxyl group or acylated with lowl @41 00B eracyl chlorides oranhydrides to the acyloxy compound in the presence of a tertiary amine such as pyr dine,

Hal

\ pyridine B 0 Ji-oooR" d. diazotized followed by a Sandmeyer type reaction ph nylglyoxylate. This in turn can be lower alkylto yield the halo group, a es $9 .2 22 9w ,al y th nd oxi ized 7.1 h

0 o C t b 4300B a) COOR" CuBr I NH Br e. diazotized and heated with an aqueous solution of 3 loweralkylsulfinyl and loweralkylsulfonyl groups or potassium iodide to prepare the 3-iodo-4-cycloallg acylated to the acylthio compounds.

B B i 0 1)HNOz 0 g xsosoom'i E c 9,. --CO0R" o 1) COOR" 2)NaOI-I I NH: SH H 0 N CH ,2 in' 'x 8 8 Q B B 5e. E,

0 o l (011:)n -CO0R" a-- (0112) COOR" son" SR" H202 A e.

B B j 0 C I (0%, -@b-ooon" 031 6 -o-o00R".--

SiOzR" SCOR" 7 WWW W TAM ylphenylglyoxylate, A second nitration or halogenation with chlorine or I bromine may be carried out on the 3-substituted-4- B 0 cycloalkylphenylglyoxylate to obtain the correspondt g coon HNo ing 3,5-disubstituted-4-cycloalkylphenylglyoxylate. Kl This may be carried out at any appropriate stage of the synthesis in order to obtain the desired substituents.

I Thus, for example, a 3-chloro-4-cycloalkylphenyl- 0 glyoxylate may be nitrated as above to obtain a 3- 1) chloro-S-nitro-4-cycloalkylphenylglyoxylate or chlorinated to obtain a 3,5-dichloro-4-cycloalkylphenylglyoxylate. A 3-nitro-4-cycloalkylphenylglyoxylate can f. diazotized followed by reaction with potassium be nitrated to give a 3,5-dinitro-4-cycloalkylphenylethylxanthate followed by hydrolysis to obtain 3- glyoxylate. A 3-alkyl compound may also be nitrated, mercapto-4-cycloalkylphenlglyoxylic acid which chlorinated or brominated to the 3-chloro, 3-bromo or can be esterified to a 3-mercapto-4 cycloalkyl- 3-nitro-5-alkyl compounds.

late can be reduced to a corresponding 3-chloro-5- 0 1):: -CO OR" B 1 B No:

0 0 1] HNO, 4 1).. COOR" (C 1 r -CO0R 0 (C 1),. G i :-ooott" HNO;// \Gh or Bra B N0, B C1(Br) o 0 a) -E-CO'OR" c a) li-oomv 1k I Alk in him, a 3-chloro-5-ni tro-4-cycioelkylphenylglyokv amino-4-cycloalkylphenylglyoxylate. This may then be monoor di-aikylated or ac ltiffii'aifi'i'fie rnziy lso be converted via the diazonium salt to a variety of de- 35 rivatives as described above.

lam Cu As a further example of disubstitution, a 3-chloro-5- 35 above products by diazotization to obtain the desired nitro-4-cycloalkylphenylglyoxylate can be reacted with cuprous cyanide in quinoline at 150C to obtain a 3- cyano-S-nitro-4-cycloalkylphenylglyoxylate; or with trifluoromethyl iodide and copper powder in quinoline at 150C to obtain a 3-trifluoromethyl-5-nitro-4- 40 cycloalkylphenylglyoxylate; or with cuprous meha v qlfitiete in. 5999 19; 7. t 50 t2, 7 a. 3r

substituents as previously described.

Various mono-substituted products may also be nitrated, chlorinated or brominated as above and again, in turn, converted to the various desired substituents. Thus, for example, a 3-fluoro-4-cycloalky1phenylglyoxylate may be nitrated or brominated and the nitro and bromo groupsconverted to various substituents. n

I B I B N02 0 O a HNO; g I I) COOR" (CH2) COOR' 1 I F F lCuCH o O b-ooon" methylsulfonyl-S-nitro-4-cycloalkylphenylglyoxylate. Still another example of various disubstitution would be the selective reduction of a 3,5-dinitro4-cycloalkylphenylglyoxylate with hydrogen or ammonium sulfide to obtain a 3-nitro-5-amino-4-cycloalkylphenylglyoxylate which in turn can be diazotized to the various de a s- V a .7

Of course, other reactions may be carried out on the H2 (Pt) sired substituents. This may be carried out on any of the nitro compounds as outlined. The diazotized products may then be hydrolyzed to the glycolic acid.

Reaction???substituted z ziasrizyigira'yigi mlate ester with a nitrogen base such as ammonia, loweralkylamine, diloweralkylamine, cycloloweralkyla mine, a nitrogen containing hetero compound such as piperidine, morpholine, piperazine, hydroxylamine and hydrazine give the corresponding amide, hydroxamic acid, or hydrazide.

loweralkylsulfonyl.

where R is lower alkyl The glycolat e esters may be hydroly zed icTtlie 6656 sponding p-cycloalkylphenylglycolic acid. Reaction of the glycolate ester or glycolic acid with an acid chloride YCl or acid anhydride YOY in the presence of a tertiary amine such as pyridine, picoline, or quinoline results in the formation of an hydroxy derivative of the HNA HzNOH on 2)n H-CONHNH2 glycolate. Examples of YCl and YOY include acetylr B R OY @h AH COOH alckOH/ YCl or YOY (Al-'0' O o v CIH'JOR" 0 B 112. R Cl NIU'R" 2:

H ncoomn" 0801B." ClS0,R" ([1 01; ncoomn" B R 0501A! ClSOgAr (l: R'. is loweralkyl an m C) 3000mm where Ar is phenyl or substituted phenyl V V i V V V O B Ono O OCOAr HCOOH(R") OCOOR" Du -HCOOH(R") (IV'OF) 0 O B R i]; OCONH: Cl ONH: 1)n HCOOH(R) OCOR" OCOCHzCHzCOOH HCOOHCR") B R B on OCOCH=CHCOOH l imcoomw) (B2) -oncoorr(n") where R is lower alkyl V The seyanagryanare may also be reacted with two" When a substituted 4-cycloalkylphenylglycolate is reacted with a phosphorus trihalide, phosphorus pentahalide, phosphorus oxyhalide, sulfurylhalide, thionyl 60 halide, or sulfur halide, the Corresponding substituted a-halo-4-cycloalkylphenylacetate is prepared.

the EQFE q sn ha d where R" is lower alkyl;

' where Hal is chloro, bromo or iodo.

Reaction of an a-sulfonate with a metal halide (preferably an alkali halide) results in the corresponding a-halo compound.

Hal

mine, a nitrogen containing hetero compound such as piperidine, morpholine, piperazine results in the correwhere Z is as described on page 4 The corresponding a-haloacetic acid may be prepared by heating the ester with acetic acid containing sponding amide. The acetate ester with hydroxylamine gives the corresponding hydroxamic acid, and with hyq a inss testh q raspr t iq ydr z dewhere R" is lower alkyl.

The acid addition salts may then be formed by the action of one equivalent of a suitable base with the substituted a-halo-4-cycloalkylphenylacetic acid. Suitable bases thus include for example the alkali metal alkox- B R. H l I B i) -lH-GOOR" Hal 6111)., -bn4mz Hal dam. -JHooz MW m where:

Z is --NH2, loweralkylamine,

diloweralkylamino, cycloloweralkylamino,

(where A is loweralkylidenyl or heteroloweralkylidenyl),

NHOH or V :Z HEHBQ.ZLW W H U Hal Hal HNOH Hal N m) Jan-comm,

where R" is lower alkyl.

The a-halo-p-cycloalkylphenylacetarnidesfqoefi' B on droxamic acids, or acethydrazides can be prepared seam from the corresponding p-cycloalkylphenyl glycola- Hm H CONHOH mides with thionyl halides according to the method of l. A. Smith, Chem. Berichle 71B: 634 (1938). 40 B R,

OzHal The substituted a-halo-p-cycloalkylphenylacetic Hal 2 J3 0 (1 acids and acid derivatives such as their salts, am- \J ides or esters may be reacted with various nucleo- R p -philic reagents which will replace the a-halogen The a-mercapto-p-cycloalkylphenylacetic acid may then be reacted with a loweralkyl chlorocarbonate, an alkali isocyanate in the presence of hydrogen chloride, a loweralkylcarbamyl chloride or a diloweralkylcarbamyl chloride to form the corresponding a-mercaptoacetic acid derivative. The a-mercapto-p-cycloulkylphenylacetic acid may also be reacted with succinic unhydride, maleic anhydride or phthalic anhydride to form the corresponding derivative.

4 B I MSH SH 3):: (EHCOOH B I SR 0 i -JJH-COOH B R Hal(0S0|R| R (06 tn ooon B R,

soon" R MBCOR" 0 1 11-00011 SCOAr MSCOA: (c 1),, H--COOH where:

R is'alkyl or aryl MW s B R S MS R" Skim H011 (]3HCOOH B R Ms ON SON z) JJHCOOH B R B R Hal(0S0:Bi) s M $01M (6H,)n) cH-co0H .L. l H1) @-'oH-00or1 B R s S0aM M o Bnn @-ha-coon S S 03M ifi coon I NH EH B R sl JNm m afl coofi where: R

M is an alkali metal salt; s IAl is lowerlalkyl;l s

r is pheny or to yl' R is alkyl or aryl. MSAOR (M) tic acid safgfiiiays repariRama; coriesisshd ing a-haloacetates, a-haloacetamides, a-haloacetic duce the dextro or Ievo form of the a-mercaptor derivative of the cycloalkylphenylacetic acid. Alternatively,

Ar is phenyl or tolyl; R is alkyl or aryl.

art that variations in the above procedures an be employed which will give that sequence of reactions which will result in the desired R, R, X and Z substituents.

These and other equivalent methods for the preparation of the acid, ester, amide, salts and a-mercapto derivatives of the instant products will be apparent to those having ordinary skill in the art.

The products of this invention may be obtained as racemic mixtures of their dextro and levorotatory isomers. These may be separated by any of the various methods of resolution. One method that may be employed is combining the racemic compound with an optically active compound by salt formation, ester formation, or amide formation to form two diastereomeric products. If the instant acids are added to an optically active base, then two diastereomeric salts are produced which possess different properties and different solubilities and can be separated by fractional crystallization. When the salts have been completely separated by repeated crystallization, the base is split off by acid hydrolysis and the pure d or I acids are obtained. Preferably, an a-mercapto derivative of a cycloalkylphenylacetic acid is reacted in alcoholic or acetone solution .with an equivalent amount of the optically active primary, secondary or tertiary amine such as cinchonidine, cinchonine, quinine, ephedrine, a-methylbenzylamine, sec-butylamine, sec-amylamine, etc. The diastereomeric amine salts produced thereby, are separated by fractional crystallization and each optically active salt is hydrolyzed with dilute mineral 'acid to pro- Of 'cbiirs''it will be understood one skilled in'the:

7 acid salts. an a-mercapto derivative of a cycloalkylphenylacetate s VA S R l]; MsiiR" s R" n.. -cH-coz B R C MSCN N (C \I)n CHCOZ I I t B R B I nauosoml) R 801M l MSOzM a n). CHCOZ o HCOZ $05M MSOsM 5 r \I)n H-COZ ssoiM MSSOSM A 3).. H-COZ NH NH B R g i C S Hs NH: J c 1).. HCOZ h S S W ere: I!

M is an alkali metal salt; si m q 8240B (M) R is lower alkyl;

z efiaysaracted with aaspseairyaaivaaaaaiy or secondary amine such as ephedrine, a-methylbenzylamine, secbutylamine, etc., to produce a mixture of diastereomeric acetamides which may be separated by fractional crystallization. Each optically active amide may be hydrolyzed with mineral acid to its respective optically active acid.

Still alternatively, an a-mercapto derivative of a cycloalkylphenylacetate may be reacted with an optically active alcohol such as l-menthol or d-borneol, or l-a-methylbenzylalcohol, to produce a mixture of diastereomeric acetate esters which may be separated by fractional crystallization. Each optically active ester may be hydrolyzed with mineral acid or alkali to its respective optically active acid. The optically active acids can also be recovered from the a-methylbenzyl esters by hydrogenolysis in the presence of palladium.

The resolution may also be carried out as above on the glycolic acid, ester or amide. The optical isomer in turn may then be converted to the a-halo compound which is then reacted as above to give the a-mercapto derivatives.

The racemic chloroacetic acids, esters and amides may also be resolved into their optical isomers by the processes described for the -mercapto acids, esters and amides.

We have found that the compounds of this invention exercise a useful degree of anti-inflammatory activity in mammals and are effective in the treatment of associated pain and fever and in like conditions which are responsive to treatment with anti-inflammatory agents. 

2. The compound Alpha -propionylthio-3-chloro-4-cyclohexylphenylacetic acid.
 3. The compound Alpha -butyrylthio-3-chloro-4-cyclohexylphenylacetic acid.
 4. The compound Alpha -butenoyl-thio-3-chloro-4-cyclohexylphenylacetic acid.
 5. The compound Alpha -benzoylthio-3-chloro-4-cyclohexylphenylacetic acid.
 6. The compound Alpha -( sigma -toluoyl-thio)-3-chloro-4-cyclohexylphenylacetic acid.
 7. The compound Alpha -( sigma -carboxybenzoylthio)-3-chloro-4-cyclohexylphenylacetic acid. 